Browsing by Author "Morinaga, O."
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Item Anti-trypanosomal activity of diarylheptanoids isolated from the bark of alnus japonica(American Journal of Chinese Medicine, 2014) Tung, N.H.; Suzuki, M.; Uto, T.; Morinaga, O.; Kwofie, K.D.; Ammah, N.; Koram, K.A.; Aboagye, F.; Edoh, D.; Yamashita, T.; Yamaguchi, Y.; Setsu, T.; Yamaoka, S.; Ohta, N.; Shoyama, Y.The crude extract of Alnus japonica bark exhibited a strong effect on the growth of Trypanosoma brucei. Subsequent chromatographic separation resulted in the isolation of two novel diarylheptanoids, known as alnuside C (2) and alnuside D (3), and three known compounds, 1-(3,4-dihydroxyphenyl)-7-(4-hydroxyphenyl)-heptan-3(R)-O-β-D-glucopyranoside (1), oregonin (4) and hirsutanone (5). The structures of the isolates were elucidated based on the use of extensive spectroscopic and chemical methods. Among the isolated diarylheptanoids, oregonin (4) (a major component of plant bark) and hirsutanone (5) exhibited potent in vitro inhibitory activity against T. brucei growth in the bloodstream with IC50 values of 1.14 and 1.78 μM, respectively. We confirmed that oregonin (4) and hirsutanone (5) were not toxic to human normal skin fibroblast cells (NB1RGB) and colon cancer cells (HCT-15) at a concentration of 50 μM; however, lower levels of toxicity were observed for leukemia cells. To determine the structure activity relationships of the isolated components, we performed Conformation Search and found that the 3-oxo function of the heptane chain in the diarylheptanoid molecule is required for their trypanocidal activity. © 2014 World Scientific Publishing Company and Institute for Advanced Research in Asian Science and Medicine.Item Antiproliferative and Pro-Apoptotic Activity of Diarylheptanoids Isolated from the Bark of Alnus japonica in Human Leukemia Cell Lines(The American Journal of Chinese Medicine, 2015-08) Uto, T.; Tung, N.H.; Appiah-Opong, R.; Aning, A.; Morinaga, O.; Edoh, D.; Nyarko, A.K.; Shoyama, Y.Alnus japonica Steud is a tree that grows in damp areas of mountain valleys and has been used as a traditional medicine in Asia. We investigated the antiproliferative activity of hirsutanone (Hir) and oregonin (Ore) in human cancer cell lines and elucidated their mechanisms of action. A cytotoxicity study using a panel of 12 human cancer and 4 normal cell lines indicated that Hir exhibited potent antiproliferative activity against 4 leukemia (Jurkat, U937, THP-1, and HL-60) and 2 colon cancer cell lines (HCT-15 and Colo205). Although Ore suppressed the cell growth of Jurkat and THP-1, its inhibitory potency was weaker than that of Hir. The IC50 values of Hir and Ore in Jurkat were 11.37 μM and 22.16 μM, respectively. Further analysis on Jurkat cells demonstrated that Hir caused a sequence of events involved in apoptosis, including nuclear morphological changes and accumulation of cells with sub-G1 DNA content. Hir led to the cleavage of poly(ADP-ribose) polymerase (PARP) and activation of caspase-3, -8, and -9. In addition, Hir-induced PARP cleavage was completely abolished by specific inhibitors to these caspases. Our data suggested that Hir is a potent antiproliferative compound against the 4 leukemia cell lines and the 2 colon cancer cell lines tested. Furthermore, Hir exerts antiproliferative actions via caspase-dependent apoptotic cell death.Item Determination of the absolute configuration of the novel anti-trypanosomal iridoid molucidin isolated from Morinda lucida by X-ray analysis(ELSEVIER, 2015-12) Karasawa, S.; Yoza, K.; Tung, N.H.; Uto, T.; Morinaga, O.; Suzuki, M.; Kwofie, K.D.; Amoa-Bosompem, M.; Boakye, D.A.; Ayi, I.; Adegle, R.; Sakyiamah, M.; Ayertey, F.; Aboagye, F.; Appiah, A.A.; Owusu, K.B.-A.; Tuffour, I.; Atchoglo, P.; Shoyama, Y.The strong anti-trypanosomal active compound, molucidin, contains a spirolactone tetracyclic iridoid skeleton and is isolated from Morinda lucida as an enantiomer of oruwacin, which is isolated from the same plant. To confirm the absolute configuration of molucidin, we prepared single crystals of molucidin for X-ray analysis. The absolute configuration of the afforded single crystal was determined by X-ray crystallography using a Cu radiation source. X-ray diffraction data were collected at 93 K in the 2θ range 7.468–134.99° and analyzed using the SHELXL-2014 program. The corresponding chiral quaternary carbon atoms in molucidin were unambiguously determined as 1R, 5S, 8S, 9S, and 10S. Notably, both enantiomers of a single molecule, molucidin and oruwacin, with a rigid structure have been isolated from the same plant species. The biosynthetic pathway for the formation of molucidin is also discussed on the basis of the absolute configuration. Our results for the first time support for structural elucidation of tetracyclic iridoids using X-ray analysis.Item New anti-trypanosomal active tetracyclic iridoid isolated from Morinda lucida Benth.(Bioorganic & Medicinal Chemistry Letters, 2015-08) Suzuki, M.; Tung, N.H.; Kwofie, K.D.; Adegle, R.; Amoa-Bosompem, M.; Sakyiamah, M.; Ayertey, F.; Owusu, K.B.-A.; Tuffour, I.; Atchoglo, P.; Frempong, K.K.; Anyan, W.K.; Uto, T.; Morinaga, O.; Yamashita, T.; Aboagye, F.; Appiah, A.A.; Appiah-Opong, R.; Nyarko, A.K.; Yamaoka, S.; Yamaguchi, Y.; Edoh, D.; Koram, K.; Ohta, N.; Boakye, D.A.; Ayi, I.; Shoyama, Y.Human African trypanosomiasis (HAT), commonly known as sleeping sickness has remained a serious health problem in many African countries with thousands of new infected cases annually. Chemotherapy, which is the main form of control against HAT has been characterized lately by the viewpoints of toxicity and drug resistance issues. Recently, there have been a lot of emphases on the use of medicinal plants world-wide. Morinda lucida Benth. is one of the most popular medicinal plants widely distributed in Africa and several groups have reported on its anti-protozoa activities. In this study, we have isolated one novel tetracyclic iridoid, named as molucidin, from the CHCl3 fraction of the M. lucida leaves by bioassay-guided fractionation and purification. Molucidin was structurally elucidated by 1H and 13C NMR including HMQC, HMBC, H–H COSY and NOESY resulting in tetracyclic iridoid skeleton, and its absolute configuration was determined. We have further demonstrated that molucidin presented a strong anti-trypanosomal activity, indicating an IC50 value of 1.27 μM. The cytotoxicity study using human normal and cancer cell lines indicated that molucidin exhibited selectivity index (SI) against two normal fibroblasts greater than 4.73. Furthermore, structure–activity relationship (SAR) study was undertaken with molucidin and oregonin, which is identical to anti-trypanosomal active components of Alnus japonica. Overlapping analysis of the lowest energy conformation of molucidin with oregonin suggested a certain similarities of aromatic rings of both oregonin and molucidin. These results contribute to the future drug design studies for HAT.Item Procyanidin trimer C1 derived from Theobroma cacao reactivates latent human immunodeficiency virus type 1 provirus.(Biochemical and Biophysical Research Communications, 2015-04) Hori, T.; Barnor, J.; Nguyen Huu, T.; Morinaga, O.; Hamano, A.; Ndzinu, J.; Frimpong, A.; Minta-Asare, K.; Amoa-Bosompem, M.; Brandful, J.; Odoom, J.; Bonney, J.; Tuffour, I.; Owusu, B.-A.; Ofosuhene, M.; Atchoglo, P.; Sakyiamah, M.; Adegle, R.; Appiah-Opong, R.; Ampofo, W.; Koram, K.; Nyarko, A.; Okine, L.; Edoh, D.; Appiah, A.; Uto, T.; Yoshinaka, Y.; Uota, S.; Shoyama, Y.; Yamaoka, S.Despite remarkable advances in combination antiretroviral therapy (cART), human immunodeficiency virus type 1 (HIV-1) infection remains incurable due to the incomplete elimination of the replication-competent virus, which persists in latent reservoirs. Strategies for targeting HIV reservoirs for eradication that involves reactivation of latent proviruses while protecting uninfected cells by cART are urgently needed for cure of HIV infection. We screened medicinal plant extracts for compounds that could reactivate the latent HIV-1 provirus and identified a procyanidin trimer C1 derived from Theobroma cacao as a potent activator of the provirus in human T cells latently infected with HIV-1. This reactivation largely depends on the NF-κB and MAPK signaling pathways because either overexpression of a super-repressor form of IκBα or pretreatment with a MEK inhibitor U0126 diminished provirus reactivation by C1. A pan-PKC inhibitor significantly blocked the phorbol ester-induced but not the C1-induced HIV-1 reactivation. Although C1-induced viral gene expression persisted for as long as 48 h post-stimulation, NF-κB-dependent transcription peaked at 12 h post-stimulation and then quickly declined, suggesting Tat-mediated self-sustainment of HIV-1 expression. These results suggest that procyanidin C1 trimer is a potential compound for reactivation of latent HIV-1 reservoirs.